In our previous application, we designed novel and rational clinical trials, based on our preclinical studies, combining gemcitabine with radiation for the treatment of patients with advanced head and neck cancers and pancreatic cancer that have produced promising clinical results. The long-term goal of this proposal is to improve upon the results of treatment of pancreatic cancer using gemcitabine and radiation through mechanistic and clinical studies of the addition of improved radiation therapy techniques and the addition of molecularly targeted therapy, in the form of EGFR antagonists. This goal will be addressed through 4 specific aims. Specific Aim 1 is to carry out new clinical trials based on our laboratory and clinical experience using gemcitabine and radiation combined with oxaliplatin. In Aim 1A, we propose to improve upon our earlier results by substituting oxaliplatin for cisplatin (based on clinical and preclinical studies), with the goal of decreasing systemic toxicity while maintaining efficacy. In Aim 1B we propose to escalate the dose of radiation, thereby increasing resectability and local control. We hypothesize that this can be accomplished safely through the application of active breathing control (ABC), to minimize organ motion, and intensity modulated radiation therapy (IMRT), to minimize the target volume. Aim 2 is to elucidate the mechanism of interaction of gemcitabine and EGFR inhibitors on cell cycle progression (Aim 2A) and on EGFR signaling (Aim 2B). Aim 3 is to optimize the combination of EGFR targeted therapy with gemcitabine and radiation in nude mice bearing human pancreatic tumors as xenografts. Aim 4 is to carry out new clinical trials based on our laboratory and clinical experience using gemcitabine, oxaliplatin and dose escalated radiation combined with EGFR targeted therapy in the treatment of locally advanced pancreatic cancer. Although this application is focused on locally advanced disease, the results should be directly applicable to patients with resectable disease;indeed we expect to increase the rate of resection for patients considered to be unresectable. We feel our preclinical and clinical team with a track record of 10 years of carrying out leading clinical trials in this area makes it likely that these studies will improve patient outcome.